Radiology and Oncology

Quantitative dynamic contrast-enhanced parameters and intravoxel incoherent motion facilitate the prediction of TP53 status and risk stratification of early-stage endometrial carcinoma

Abstract Background The aim of the study was to investigate the value of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and intravoxel incoherent motion (IVIM) in differentiating TP53-mutant from wild type, low-risk from non-low-risk early-stage endometrial carcinoma (EC). Patients and methods A total of 74 EC patients underwent pelvic MRI. Parameters volume transfer constant (K trans ), rate transfer constant (K ep ), the volume of extravascular extracellular space per unit volume of tissue (V e ), true diffusion coefficient (D), pseudo-diffusion coefficient (D*), and microvascular volume fraction (f) were compared. The combination of parameters was investigated by logistic regression and evaluated by bootstrap (1000 samples), receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA). Results In the TP53-mutant group, K trans and K ep were higher and D was lower than in the TP53-wild group; K trans , V e , f, and D were lower in the non-low-risk group than in the low-risk group (all P < 0.05). In the identification of TP53-mutant and TP53-wild early-stage EC, K trans and D were independent predictors, and the combination of them had an optimal diagnostic efficacy (AUC, 0.867; sensitivity, 92.00%; specificity, 80.95%), which was significantly better than D (Z = 2.169, P = 0.030) and K trans (Z = 2.572, P = 0.010). In the identification of low-risk and non-low-risk early-stage EC, K trans , V e , and f were independent predictors, and the combination of them had an optimal diagnostic efficacy (AUC, 0.947; sensitivity, 83.33%; specificity, 93.18%), which was significantly better than D (Z = 3.113, P = 0.002), f (Z = 4.317, P < 0.001), K trans (Z = 2.713, P = 0.007), and V e (Z = 3.175, P = 0.002). The calibration curves showed that the above two combinations of independent predictors, both have good consistency, and DCA showed that these combinations were reliable clinical prediction tools. Conclusions Both DCE-MRI and IVIM facilitate the prediction of TP53 status and risk stratification in early-stage EC. Compare with each single parameter, the combination of independent predictors provided better predictive power and may serve as a superior imaging marker.

Evaluation of the training program for p16/ Ki-67 dual immunocytochemical staining interpretation for laboratory staff without experience in cervical cytology and immunocytochemistry

Abstract Background p16/Ki-67 dual immunocytochemical staining (DS) is considered easy to interpret if evaluators are properly trained, however, there is no consensus on what constitutes proper training. In the present study we evaluated a protocol for teaching DS evaluation on students inexperienced in cervical cytology. Methods Initial training on 40 DS conventional smears was provided by a senior cytotechnologist experienced in such evaluation. Afterwards, two students evaluated 118 cases. Additional training consisted mainly of discussing discrepant cases from the first evaluation and was followed by evaluation of new 383 cases. Agreement and accuracy of students’ results were compared among the participants and to the results of the reference after both evaluations. We also noted time needed for evaluation of one slide as well as intra-observer variability of the teacher’s results. Results At the end of the study, agreement between students and reference was higher compared to those after initial training (overall percent agreement [OPA] 81.4% for each student, kappa 0.512 and 0.527 vs . OPA 78.3% and 87.2%, kappa 0.556 and 0.713, respectively). However, accuracy results differed between the two students. After initial training sensitivity was 4.3% points and 2.9% points higher, respectively compared to the reference, while specificity was 30.6% points and 24.4% points lower, respectively, compared to the reference. At the end of the study, the sensitivity reached by one student was the same as that of the reference, while it was 2.6% points lower for the other student. There was a statistically significant difference in specificity between one student and the reference and also between students (16.7 and 15.1% points). Towards the end of the study, one student needed 5.2 min for evaluating one slide while the other needed 8.2 min. The intra-observer variability of the senior cytotechnologist was in the range of “very good” in both arms of the study. Conclusions In teaching DS evaluation, the students’ progress has to be monitored using several criteria like agreement, accuracy and time needed for evaluating one slide. The monitoring process has to continue for a while after students reach satisfactory results in order to assure a continuous good performance. Monitoring of teacher’s performance is also advisable.

Quality of life of women with recurrent vulvar cancer treated with electrochemotherapy

Abstract Background The quality of life of patients undergoing oncologic treatment has become an important issue in recent years. Owing to potential mutilation following surgery for vulvar cancer, more conservative approaches have evolved with the integration of new local ablative therapies, such as electrochemotherapy. The aim of this study was to determine the quality of life of women with vulvar cancer recurrence treated with electrochemotherapy for nonpalliative purposes. Patients and methods Eleven patients with vulvar cancer recurrence were treated with electrochemotherapy from July 2020 to December 2023. Patients completed different questionnaires: the EuroQol - 5 Dimension (EQ-5D), European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Vulva Cancer 34 (EORTC QLQ-VU34) and visual analog pain scale (VAS) before and one, three and six months after electrochemotherapy. As a control group, fifteen patients with vulvar cancer recurrence treated with wide local excision completed the EORTC QLQ-C30 and VAS questionnaires before surgery and three and six months after surgery. Results No significant differences in EQ-5D scores were found between quality of life before electrochemotherapy and at each follow-up visit. A comparison of the EORTC QLQ-C30 scores between the electrochemotherapy and surgery groups showed a significant difference in physical functioning, fatigue, insomnia, and global health status three months after the procedure and in role, cognitive, social functioning and appetite loss six months after the procedure, all of which were in favor of the electrochemotherapy group. The EORTC QLQ-VU34 questionnaire showed improvements in urinary symptoms and symptoms related to scarring and mutilation of the external genitalia in the electrochemotherapy group. The VAS score did not differ significantly between the electrochemotherapy and surgical groups. Conclusions The study showed that the quality of life after treatment with electrochemotherapy is better in some segments than after surgical treatment.

Treatment of vulvar cancer recurrences with electrochemotherapy – a detailed analysis of possible causes for unsuccessful treatment

Abstract Background Electrochemotherapy has good local effectiveness in the treatment of vulvar cancer. Most studies have reported the safety and effectiveness of electrochemotherapy for palliative treatment of gynecological cancers and mostly vulvar squamous cell carcinoma. Some tumors, however, fail to respond to electrochemotherapy. The biological features/determinants for the nonresponsiveness are not determined yet. Patient and methods A recurrence of vulvar squamous cell carcinoma was treated by electrochemotherapy using intravenous administration of bleomycin. The treatment was performed by hexagonal electrodes according to standard operating procedures. We analyzed the factors that could determine nonresponsiveness to electrochemotherapy. Results Based on the presented case of nonresponsive vulvar recurrence to electrochemotherapy, we hypothesize that the vasculature of the tumors prior to treatment may predict the response to electrochemotherapy. The histological analysis showed minimal presence of blood vessels in the tumor. Thus, low perfusion may reduce drug delivery and lead to a lower response rate because of the minor antitumor effectiveness of vascular disruption. In this case, no immune response in the tumor was elicited by electrochemotherapy. Conclusions In this case, of nonresponsive vulvar recurrence treated by electrochemotherapy, we analyzed possible factors that could predict treatment failure. Based on histological analysis, low vascularization of the tumor was observed, which hampered drug delivery and distribution and resulted in no vascular disrupting action of electro-chemotherapy. All these factors could contribute to ineffective treatment with electrochemotherapy.

Cervix-Online computer program: 27 years of hospital-based clinical registry for cervical cancer at the University Medical Centre Maribor

Abstract Background Clinical registries are designed to collect quality data about the care for cancer patients in order to improve it. They gather data that are generated during diagnosis and cancer treatment and also post-treatment follow-up. Analysis of collected data allows an improvement in the quality of patient care and a comparison with other health care providers. The aim of the present article is to describe the current version and practice of hospital-based cervical cancer registry in UKC Maribor. Materials and methods The first questionnaire for monitoring patients with cervical cancer was introduced at the Department of Gynecologic and Breast Oncology of the Maribor General Hospital in 1994. Since then, the principles for treating cervical cancer have been revised on several occasions. Therefore, based on our experience and new approaches to treatment, we have frequently amended the questionnaire content. It was redesigned into a form that is currently in use and transformed into a Cervix-Online computer program in 2014. Results Over the last 27 years, we have collected data on cervical cancer patients treated at the University Medical Centre Maribor and former Maribor General Hospital. The Cervix-Online computer program that was developed for this purpose enabled a rapid and reliable collection, processing and analysis of 116 different data of patients with cervical cancer, including general data, history, diagnostic procedures, histopathological examination results, treatment methods, and post-treatment follow-ups. Conclusions The hospital-based cervical cancer registry with Cervix-Online computer program enables the collection of data to enhance diagnosis and the treatment of cervical cancer patients, the organization of day-to-day service, as well as the comparison of our treatment results with national and international standards. Incomplete or incorrect data entry, however, might pose a limitation of the clinical registry, which depends on several healthcare professionals involved in the diagnostic procedures, treatment, and follow-up of cervical cancer patients.

Modern treatment of vulvar cancer

Abstract Background Vulvar cancer accounts for 3–5% of malignant diseases of the female genital tract. The Slovenian incidence rate is 5.5/100,000, which means 57 new cases per year. The most common histological type (90%) is squamous cell carcinoma. Based on etiology, it can be classified into the first type which correlates with human papillomavirus (HPV) infection and the second type which is not associated with HPV. The most common and long-lasting symptom of vulvar cancer is pruritus. The preferred diagnostic procedure to confirm the diagnosis is a punch or incision biopsy. Surgery in combination with radiotherapy is the standard treatment for vulvar cancer. Sentinel lymph node biopsy with lymphoscintigraphy is now a standard part of surgical treatment. Chemotherapy is a palliative treatment option. Conclusions Vulvar cancer is a rare disease. Because of the pathogenesis, surgery and radiotherapy are the main treatment modalities. The sentinel node biopsy (SNB) represents a contemporary approach to the vulvar cancer treatment and significantly reduces morbidity. Improvements in treatment of vulvar cancer contributed to the decrease of mortality among Slovenian women.

Anastomosing hemangioma of the ovary – a comprehensive review of this rare ovarian entity

Abstract Background Anastomosing hemangioma of the ovary is a rare vascular tumor that predominantly affects middle-aged women. Despite its benign nature, its histological appearance can mimic aggressive vascular lesions, posing diagnostic challenges. This review aims to provide an overview of this uncommon entity. Methods The PubMed and Scopus databases were searched for relevant articles published in English. Information on all retrieved cases was extracted and reviewed in detail. Results We found 33 cases with relevant details of anastomosing heamangioma of the ovary. Despite the small number of cases we found, our study demonstrated the importance of an accurate hystopathological evaluation. Conclusions Although the preliminary imaging and initial microscopic features may appear alarming, careful microscopic examination reveals benign behavior. There is a need to raise awareness of this unusual and rare entity to improve morphologic recognition and avoid misdiagnosis that could lead to unnecessary treatment or patient anxiety.

The prognostic significance of tumor-immune microenvironment in ascites of patients with high-grade serous carcinoma

Abstract Background High-grade serous carcinoma (HGSC) is often associated with ascites at presentation. Our objective was to quantify immune cells (ICs) in ascites prior to any treatment was given and evaluate their impact on progression-free survival (PFS) and overall survival (OS). Patients and methods Forty-seven patients with primary HGSC and ascites were included. Flow-cytometric analysis was performed to detect percentages of CD3 + T cells (CD4 + , CD8 + , Tregs, and NKT cells), B cells, NK cells (CD56 bright CD16 − and CD56 dim CD16 + subsets), macrophages and dendritic cells (DCs). Furthermore, CD103 expression was analyzed on T cells and their subsets, while PD-1 and PD-L1 expression on all ICs. Cut-off of low and high percentages of ICs was determined by the median of variables, and correlation with PFS and OS was calculated. Results CD3 + cells were the predominant ICs (median 51%), while the presence of other ICs was much lower (median ≤10%). CD103 + expression was mostly present on CD8 + , and not CD4 + cells. PD-1 was mainly expressed on CD3 + T cells (median 20%), lower expression was observed on other ICs (median ≤10%). PD-L1 expression was not detected. High percentages of CD103 + CD3 + T cells, PD-1 + Tregs, CD56 bright CD16 − NK cells, and DCs correlated with prolonged PFS and OS, while high percentages of CD8 + cells, macrophages, and PD-1 + CD56 bright CD16 − NK cells, along with low percentages of CD4 + cells, correlated with better OS only. DCs were the only independent prognostic marker among all ICs. Conclusions Our results highlight the potential of ascites tumor-immune microenvironment to provide additional prognostic information for HGSC patients. However, a larger patient cohort and longer follow-up are needed to confirm our findings.

Efficacy of transvaginal ultrasound versus magnetic resonance imaging for preoperative assessment of myometrial invasion in patients with endometrioid endometrial cancer: a prospective comparative study

Abstract Background We compared the accuracy of preoperative transvaginal ultrasound (TVUS) versus magnetic resonance imaging (MRI) for the assessment of myometrial invasion (MI) in patients with endometrial cancer (EC), while definitive histopathological diagnosis served as a reference method. Patients and methods Study performed at a single tertiary centre from 2019 to 2021, included women with a histopathological proven EC, hospitalized for scheduled surgery. TVUS and MRI were performed prior to surgical staging for assessment MI, which was estimated using two objective TVUS methods (Gordon’s and Karlsson’s) and MRI. Patients were divided into two groups, after surgery and histopathological assessment of MI: superficial (≤ 50%) and deep (> 50%). Results Sixty patients were eligible for the study. According to the reference method, there were 34 (56.7%) cases in the study with MI < 50%, and 26 (43.3%) with MI > 50%. Both objective TVUS methods and MRI showed no statistical significant differences in overall diagnostic performance for the preoperative assessment of MI. The concordance coefficient between both TVUS methods, MRI and histopathology was statistically significant (p < 0.001). Gordon’s method calculating MI reached a positive predictive value (PPV) of 83%, negative predictive value (NPV) of 83%, 77% sensitivity, 88% specificity, and 83% overall accuracy. Karlsson’s method reached PPV of 82%, NPV of 79%, 69% sensitivity, 88% specificity, and 80% overall accuracy. Accordingly, MRI calculating MI reached PPV of 83%, NPV of 97%, 97% sensitivity, 85% specificity, and 90% overall accuracy. Conclusions We found that objective TVUS assessment of myometrial invasion was performed with a diagnostic accuracy comparable to that of MRI in women with endometrial cancer.

Pre-treatment risk assessment of women with endometrial cancer: differences in outcomes of molecular and clinical classifications in the Slovenian patient cohort

Abstract Background The aim of this study was to evaluate changes in prognostic risk profiles of women with endometrial cancer by comparing the clinical risk assessment with the integrated molecular risk assessment profiling. Patients and methods This prospective study recruited patients with biopsy proven endometrial cancer treated at the University Medical Centre Maribor between January 2020 to February 2021. Patient clinical data was assessed and categorized according to the currently valid European Society of Gynaecological Oncology, European SocieTy for Radiotherapy and Oncology, and European Society of Pathology (ESGO/ESTRO/ESP) guidelines on endometrial cancer. Molecular tumour characterization included determination of exonuclease domain of DNA polymerase-epsilon (POLE) mutational status by Sanger sequencing and imunohistochemical specimen evaluation on the presence of mismatch repair deficiencies (MMRd) and p53 abnormalities (p53abn). Results Fourty-five women were included in the study. Twenty-two tumours were of non-specific mutational profile (NSMP) (56.4%), 13 were classified as MMRd (33.3%), 3 were classified as p53abn (7.7%) and 1 was classified as POLE mutated (2.6%). Six tumours (15.4%) had multiple molecular classifiers, these were studied separately and were not included in the risk assessment. The clinical risk-assessment classified 21 women (53.8%) as low-risk, 5 women (12.8%) as intermediate risk, 2 women as high-intermediate risk (5.1%), 10 women (25.6%) as high risk and 1 patient as advanced metastatic (2.6%). The integrated molecular classification changed risk for 4 women (10.3%). Conclusions Integrated molecular risk improves personalized risk assessment in endometrial cancer and could potentially improve therapeutic precision. Further molecular stratification with biomarkers is especially needed in the NSMP group to improve personalized risk-assessment.

Surgical treatment and fertility perservation in endometrial cancer

Abstract Background Endometrial cancer (EC) represents a high health burden in Slovenia and worldwide. The incidence is increasing due to lifestyle and behavioural risk factors such as obesity, smoking, oestrogen exposure and aging of the population. In many cases, endometrial cancer is diagnosed at an early stage due to obvious signs and symptoms. The standard treatment is surgery with or without adjuvant therapy, depending on the stage of the disease and the risk of recurrence. However, treatment modalities have changed in the last decades, considerably in the extent of lymphadenectomy. Conclusions The gold standard of treatment for is surgery, which may be the only treatment modality in the early stages of low-grade tumours. In recent years, a minimally invasive approach with sentinel node biopsy (SNB) has been proposed. A conservative approach with hormonal treatment is used if fertility preservation is desired. If EC is in advance stage, high-risk histology, or high grade, radiotherapy, chemotherapy, or a combination of both is recommended.

The prevalence of occult ovarian cancer in the series of 155 consequently operated high risk asymptomatic patients – Slovenian population based study

Abstract Background We assessed the prevalence, localization, type and outcome of occult cancer at risk-reducing salpingo-oophorectomy or salpingectomy (RRSO) in asymptomatic carriers of pathogenic or likely pathogenic BRCA1/2 variants and high-risk BRCA1/2 negative women. Patients and methods A retrospective analysis of all consecutive gynaecologic preventive surgeries from January 2009 to December 2015 was performed. Participants underwent genetic counselling and BRCA1/2 testing before the procedure. Data on clinical parameters, adjuvant treatment and follow-up were collected and analysed. Results One hundred and fifty-five RRSO were performed in 110 BRCA1 , 35 BRCA2 carriers of pathogenic or likely pathogenic variants and 10 high-risk BRCA1/2 negative women, at the mean age of 48.3 years. Nine occult cancers (9/155, 5.8%) were identified; eight in BRCA1 positive women and one in high-risk BRCA1/2 negative woman. We identified four non-invasive serous intraepithelial tubal carcinomas (3 in BRCA1 carriers and 1 in a high-risk BRCA1/2 negative woman) and five invasive tubo-ovarian high grade serous cancers (all detected in BRCA1 carriers). Only one out of nine patients (11.1%) with occult cancer had a slightly elevated CA-125 value preoperatively. Conclusions A 5.8% prevalence of occult invasive and noninvasive tubo-ovarian serous cancer after RRSO was found in high risk asymptomatic and screen negative women. We conclude that RRSO should be performed in BRCA1/2 carriers and in high-risk BRCA1/2 negative women. Age of preventive gynaecologic surgery should be carefully planned, taking into account the completion of childbearing age and type of mutation. The results favour the tubal hypothesis of tubal origin of high grade serous ovarian and peritoneal cancer. Cytology result of peritoneal cavity washing was important for the decision making process in determining treatment. Cytology examination should be performed in all cases of RRSO. CA-125 assay did not prove to be an effective screening tool for early cancer detection in our patients.

Human papillomavirus (HPV) genotyping and prognostic value of HPV E4 protein and transcription factors NANOG and SOX11 in atypical p16 patchy squamous epithelium of cervix

Abstract Background Immunohistochemical staining for p16 is used to differentiate precancerous cervical lesions in tissue samples, but the interpretation of patchy p16 expression remains challenging. We performed human papillomavirus (HPV) genotyping and evaluated immunohistochemical expression of HPV E4 protein – a marker for transient infections, stem cell transcription factor NANOG, and transcription factor SOX11 to detect possible high-grade squamous lesions in atypical p16 patchy squamous epithelium. Materials and methods We analyzed 24 cervical tissue samples with atypical squamous epithelium and patchy p16 expression along with the following controls: 11 cases of atypical squamous epithelium with null p16 expression, 9 condylomas, 12 cases of cervical intraepithelial neoplasia (CIN) grade 1, 11 cases of CIN2, and 9 cases of CIN3. In addition, HPV genotyping of tissue and related cervical smears from up to two years prior to biopsy was performed. Immunohistochemical staining for Ki67, HPV E4, NANOG, and SOX11 was performed and compared with follow-up data. Results High-risk HPV infection was detected in 6/24 cases with patchy p16 expression and HPV E4 was expressed in 1/24 cases with patchy p16, weak NANOG expression was found in 11/24 cases with patchy p16 expression while no SOX11 expression was observed. During 10 months of follow-up, additional CIN1 and two CIN3 were identified, and another CIN1 and CIN3 after 5 and 6 years, accordingly. Conclusions Our study showed that atypical squamous epithelium with patchy p16 expression poses a risk for highgrade precancerous lesions, harbouring high-risk HPV infection. Novel markers may hold diagnostic value in other specific contexts.

Expression of the stem cell markers NANOG and SOX2 in the cervical squamous carcinogenesis

Abstract Background The aim of the present study was to assess a diagnostic potential of stem cell markers NANOG and SOX2 for classifying cervical squamous intraepithelial lesions (SILs)/cervical intraepithelial neoplasia (CIN). Patients and methods NANOG and SOX2 expression was evaluated immunohistochemically on 40 patients: in 10 cases each of low-grade SIL (LSIL), high-grade SIL/CIN, grade 2 (HSIL/CIN 2), HSIL/CIN, grade 3 (HSIL/CIN 3), cervical squamous cell carcinoma (CSCC) and their adjacent non-dysplastic squamous epithelium. In addition, human papillomavirus (HPV) genotyping and immunohistochemical staining with p16 and Ki-67 were done. NANOG and SOX2 expression was compared between squamous lesions and controls and between squamous lesions by multiplying staining intensity (SI) by the percentage of positive cells (P) and by multiplying SI by the thickness of staining in epithelium (T) to calculate SI x P and SI x T score. Results NANOG and SOX2 expression gradually increased from non-dysplastic squamous epithelium via LSIL and HSIL to CSCC. Expression of NANOG and SOX2 was higher in LSIL compared to controls (P < 0.05 for NANOG Si x P and Si x T scores and SOX2 SI x T score) and lower compared to HSIL (P < 0.05 for all SI x P and SI x T scores). HSIL/CIN 3 showed higher SOX2 expression than HSIL/CIN 2 (P < 0.05 for SI x P and SI x T scores). Conclusions Contrary to p16, NANOG and SOX2 could be effective for distinguishing LSIL from non-dysplastic changes. NANOG and SOX2 could be surrogate markers for differentiating LSIL from HSIL. Moreover, SOX2 could be helpful for distinguishing HSIL/CIN 2 from HSIL/CIN 3. Further studies with larger numbers of patients and molecular insights are needed.

Preoperative serum CA-125 level as a predictor for the extent of cytoreduction in patients with advanced stage epithelial ovarian cancer

Abstract Background Ovarian cancer is the seventh most common cancer in women worldwide and the eighth most common cause of cancer death. Due to the lack of effective early detection strategies and the unspecific onset of symptoms, it is diagnosed at an advanced stage in 75% of cases. The cancer antigen (CA) 125 is used as a prognostic marker and its level is elevated in more than 85% of women with advanced stages of epithelial ovarian cancer (EOC). The standard treatment is primary debulking surgery (PDS) followed by adjuvant chemotherapy (ACT), but the later approach is neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS). Several studies have been conducted to find out whether preoperative CA-125 serum levels influence treatment choice, surgical resection and survival outcome. The aim of our study was to analyse experience of single institution as Cancer comprehensive center with preoperative usefulness of CA-125. Patients and methods At the Institute of Oncology Ljubljana a retrospective analysis of 253 women with stage FIGO IIIC and IV ovarian cancer was conducted. Women were divided into two groups based on their primary treatment. The first group was the NACT group (215 women) and the second the PDS group (38 women). The differences in patient characteristics were compared using the Chi-square test and ANOVA and the Kaplan-Meier method was used for calculating progression-free survival (PFS) and overall survival (OS). Results The median serum CA-125 level was higher in the NACT group than in the PDS group, 972 IU/ml and 499 IU/ ml, respectively. The PFS in the NACT group was 8 months (95% CI 6.4–9.5) and 18 months (95% CI 12.5–23.4) in the PDS group. The median OS was lower in the NACT group than in the PDS group, 25 months (95% CI 20.6–29.5) and 46 months (95% CI 32.9–62.1), respectively. Conclusions Preoperative CA-125 cut off value of 500 IU/ml is a promising threshold to predict a successful PDS.

Long term results of follow-up after HPV self-sampling with devices Qvintip and HerSwab in women non-attending cervical screening programme

Abstract Background We are presenting the results of the Slovenian human papillomaviruses (HPV) self-sampling pilot study in colposcopy population of National Cervical Cancer Screening Programme ZORA for the first time. One-year and four-year follow-up results are presented for two different self-sampling devices. Participants and methods A total of 209 women were enrolled in the study at colposcopy clinic. Prior to the gynaecological examination, all women performed self-collected vaginal swab at the clinic; 111 using Qvintip and 98 using HerSwab self-sampling device. After self-sampling, two cervical smears were taken by a clinician; first for conventional cytology and second for HPV test. After that, all women underwent colposcopy and a cervical biopsy if needed. We compared sensitivity, specificity, and predictive values of cytology (at the cut-off atypical squamous cells of undetermined significance or more [ASC-US+]) and HPV test (on self- and clinician-taken samples) for the detection of cervical intraepithelial neoplasia grade 2 or more (CIN2+) after one and four years of follow-up. Hybrid Capture 2 (HC2) assay was used for all HPV testing. Results The mean age of 209 women was 37.6 years and HPV positivity rate 67.0% (140/209), 36.9 years and 70.3% (78/111) in the Qvintip group and 38.4 years and 63.3% (62/98) in the HerSwab group, respectively. Overall, percent agreement between self and clinician-taken samples was 81.8% (kappa 0.534) in the Qvintip and 77.1% (kappa 0.456) in the HerSwab group. In the Qvintip group, the longitudinal sensitivity, specificity, positive and negative predictive values were 71.8%, 75.0%, 83.6%, 60.0% for cytology; 83.1%, 51.3%, 75.6% and 62.5% for HPV test of self-taken samples and 94.4%, 57.5%, 79.8% and 85.2% for HPV test on clinician-taken samples. In the HerSwab group, the corresponding results were 71.7%, 46.7%, 61.3%, 58.3% for cytology; 75.0%, 47.7%, 62.9% and 61.8% for HPV test on self-taken samples and 94.3%, 44.4%, 66.7% and 87.0% for clinician-taken samples, respectively. Conclusions The results confirm that HPV self-sampling is not as accurate as clinician sampling when HC2 is used. All HPV tests showed a higher sensitivity in detecting CIN2+ compared to cytology. Due to non-inferior longitudinal sensitivity of HPV self-sampling compared to cytology, HPV self-sampling might be an option for non-attenders to the National Cancer Screening Programme.

FDG PET-CT as an important diagnostic tool and prognostic marker in suspected recurrent cervical carcinoma after radiotherapy: comparison with MRI

Abstract Background Recurrent disease in post-irradiation patients with cervical cancer is often difficult to delineate on magnetic resonance imaging (MRI), because posttreatment changes can have a similar appearance, and further evaluation is often required. The aims of the study were to evaluate positron emission tomography/computed tomography with 18F-fluorodeoxyglucose (FDG PET-CT) diagnostic role in suspected recurrent cervical cancer after radiotherapy, compare it to MRI, and assess their prognostic impact in these patients. Patients and methods This cohort retrospective study included patients previously treated with radiotherapy for carcinoma of uterine cervix with suspected recurrence, who had undergone MRI of abdomen and pelvis, and were subsequently evaluated on FDG PET-CT, with minimum follow-up period of 12 months. Results In the total of 84 patients included in analysis, MRI vs . FDG PET-CT showed sensitivity, specificity and accuracy of 80.1%, 52.4% and 66.7%, vs . 97.6%, 61.9% and 79.8%, respectively. Patients with positive findings on MRI (Log Rank, p = 0.003) and PET-CT (Log Rank, p < 0.001) had shorter progression-free survival (PFS) than those with negative results. In univariate Cox regression models, MRI and FDG PET-CT results were found to be related to PFS (p = 0.005 and p < 0.001, respectively). However, multivariate analysis proved only FDG PET-CT to be independent prognostic factor, where patients with positive FDG PET-CT results had almost nine times higher risk of progression (p < 0.001). Conclusion FDG PET-CT represents useful diagnostic tool in suspected recurrent cervical cancer after radiotherapy, showing high sensitivity in its detection. In addition, it is an independent factor in predicting progression-free survival in these patients.

Identification of women with high grade histopathology results after conisation by artificial neural networks

Abstract Background The aim of the study was to evaluate if artificial neural networks can predict high-grade histopathology results after conisation from risk factors and their combinations in patients undergoing conisation because of pathological changes on uterine cervix. Patients and methods We analysed 1475 patients who had conisation surgery at the University Clinic for Gynaecology and Obstetrics of University Clinical Centre Maribor from 1993–2005. The database in different datasets was arranged to deal with unbalance data and enhance classification performance. Weka open-source software was used for analysis with artificial neural networks. Last Papanicolaou smear (PAP) and risk factors for development of cervical dysplasia and carcinoma were used as input and high-grade dysplasia Yes/No as output result. 10-fold cross validation was used for defining training and holdout set for analysis. Results Bas eline classification and multiple runs of artificial neural network on various risk factors settings were performed. We achieved 84.19% correct classifications, area under the curve 0.87, kappa 0.64, F-measure 0.884 and Matthews correlation coefficient (MCC) 0.640 in model, where baseline prediction was 69.79%. Conclusions With artificial neural networks we were able to identify more patients who developed high-grade squamous intraepithelial lesion on final histopathology result of conisation as with baseline prediction. But, characteristics of 1475 patients who had conisation in years 1993–2005 at the University Clinical Centre Maribor did not allow reliable prediction with artificial neural networks for every-day clinical practice.

Diagnostic performance of p16/Ki-67 dual immunostaining at different number of positive cells in cervical smears in women referred for colposcopy

Abstract Background The aim of the study was to evaluate the diagnostic accuracy of p16/Ki-67 dual immunostaining (p16/ Ki-67 DS) in cervical cytology and the number of positive p16/Ki-67 cells to diagnose high grade cervical intraepithelial neoplasia (CIN2+) in colposcopy population. Subjects and methods We performed an analysis on a subset cohort of 174 women enrolled within a large-scale randomised controlled human papillomavirus (HPV) self-sampling project organised as part of the population-based Cervical Cancer Screening Programme ZORA in Slovenia. This subset cohort of patients was invited to the colposcopy clinic, underwent p16/Ki-67 DS cervical cytology and had the number of p16/Ki-67 positive cells determined. Results Among analysed women, 42/174 (24.1%) had histologically confirmed CIN2+. The risk for CIN2+ was increasing with the number of positive cells (p < 0.001). The sensitivity of p16/Ki-67 DS for detection of CIN2+ was 88.1%, specificity was 65.2%, positive predictive value was 44.6% and negative predictive value was 94.5%. Conclusions Dual p16/Ki-67 immunostaining for the detection of CIN2+ has shown high sensitivity and high negative predictive value in our study, which is comparable to available published data. The number of p16/Ki-67 positive cells was significantly associated with the probability of CIN2+ detection. We observed a statistically significant and clinically relevant increase in specificity if the cut-off for a positive test was shifted from one cell to three cells.

Tumoral volume measured preoperatively by magnetic resonance imaging is related to survival in endometrial cancer

Abstract Background The aim of the study was to determine if the endometrial tumor volume (TV) measured by magnetic resonance imaging (MRI-TV) is associated with survival in endometrial cancer and lymph nodes metastases (LN+). Patients and methods We evaluated the MRI imaging and records of 341 women with endometrial cancer and preoperative MRI from 2008 to 2018. The MRI-TV was calculated using the ellipsoid formula measuring three perpendicular tumor diameters. Tumor myometrial invasion was also analyzed. Results Higher MRI-TV was associated with age ≥ 65y, non-endometrioid tumors, grade-3, deep-myometrial invasion, LN+ and advanced FIGO stage. There were 37 patients with LN+ (8.8%). Non-endometrioid tumors, deep-myometrial invasion, grade-3 and MRI-TV ≥ 10 cm 3 were the factors associated with LN+. Using a receiver operating characteristic [ROC] curve, the MRI-TV cut-off for survival was 10 cm 3 (area under curve [AUC] = 0.70; 95% CI: 0.61–0.73). 5 years disease-free (DFS) and overall survival (OS) was significantly lower in MRI-TV ≥ 10 cm 3 (69.3% vs . 84.5%, and 75.4% vs . 96.1%, respectively). MRI-TV was considered an independent factor of DFS (HR: 2.20, 95% CI: 1.09–4.45, p = 0.029) and OS (HR: 3.88, 95% CI: 1.34–11.24, p = 0.012) in multivariate analysis. Conclusions MRI-TV was associated with LN+, and MRI-TV ≥ 10 cm 3 was an independent prognostic factor of lower DFS and OS. The MRI-TV can be auxiliary information to plan the surgery strategy and predict the adjuvant treatment in women with endometrial cancer.